This proposal suggests a series of detailed studies on the interaction between various ions shown by the potassium conductance (primarily) of the axolemma. Experiments will be performed on isolated, perfused squid giant axon using a conventional axial wire voltage clamp. A microcomputer will control delivery of command pulse protocols and data acquisition. Insofar as possible, experiments are designed to avoid periaxonal potassium accumulation and changes in ionic strength as the concentration of an ion under study is varied. Thus, two factors that frequently complicate quantitative analysis of studies on the potassium conductance will be eliminated. Six general questions are posed for study. (1) Do alkali cations interact only with the open K channel, or do they also affect gating? (2) How do K ions interact with blocking ions on the cis and trans sides of the membrane? (3) How does the molecular structure of an organic ion influence the voltage dependence and potency of its effect on the potassium conductance? (4) What are the relative affinities of different freely permeant ions for the K channel? (5) Does temperature modify the kinetics and affinity of binding by various agents? (6) What energetic profiles, posed by the membrane to various interacting ions, are sufficient to quantitatively account for the above effects? Predictions of likely possibilities will be examined using rate theory calculations. The detailed account of kinetics, voltage dependence and potency of action of these various agents will place important functional restrictions on possible molecular structures for the potassium channel that will undoubtedly be put forward in the future.